Mechanical ventilation supports the lung's vital gas exchange function for the period necessary to resolve acute lung injury (ALI). Poorly selected patterns of ventilation, however, have the potential to extend damage or impede healing. The ultimate objective of this project is to determine how to minimize iatrogenic damage and speed recovery in ALI. Our strategy is to first achieve a firm understanding of the underlying principles of ventilator-induced lung injury (VILI) through mechanism-defining research, then to test clinically relevant interventions in a laboratory setting, and finally to bring them to the bedside. In translating scientific observation to clinical practice, we take advantage of our own expertise in cardiopulmonary mechanisms and clinical management, draw upon the basic science expertise of our University campus-based SCOR colleagues, and interface with international colleagues who expand our investigative capabilities. Two of our previous observations drive the investigations of the current proposal: 1) VILI is a regionalized process that concentrates in dependent zones of the lung. 2) The severity of VILI is influenced by non-ventilatory co-interventions relevant to the clinical setting: position, body temperature, and perfusion pressure. Our laboratory work will proceed along three complementary lines using small and large animal models to address pressing clinical questions related to the determinants and consequences of VILI: 1) The chronology, adaptive processes, and co- interventions that influence VILI. 2) The effectiveness of specific ventilatory patterns and maneuvers intended to optimize regional and global lung recruitment, an objective of fundamental importance in avoiding VILI and speeding the resolution of ALI. 3) The remote systemic effects of VILI which occur in the setting of pre-existing or developing pneumonia. Our clinical projects focus on optimizing lung recruitment, with special attenuation to re-expanding dependent and peridiaphragmatic regions, those most vulnerable to collapse. In conducting these studies, we will employ specialized techniques that enable detailed investigation of regional mechanics and lung damage: 1) Measurement of local pleural surface pressure using thin flexible air-filled sensors ("wafers"). 2) Computer-aided tomographic imaging and densitometry. 3) A ventilated and perfused isolated heart-lung preparation that allows on-line monitoring of lung damage and precise regulation of perfusion characteristics.